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Background: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy., Methods: In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR -mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed., Results: A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents., Conclusions: First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR -mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone., Patients and Methods: Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, -10% for the difference in the overall CR rate)., Results: Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% ( P < .001) and 0.3% versus 3.6% ( P < .001), respectively., Conclusion: FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting., Competing Interests: Akito HataConsulting or Advisory Role: Boehringer Ingelheim, Lilly, Chugai Pharma, AstraZeneca, MSDSpeakers' Bureau: Boehringer Ingelheim, Lilly, Chugai Pharma, AstraZeneca, Taiho PharmaceuticalResearch Funding: Boehringer Ingelheim (Inst), MSD (Inst), Lilly (Inst), AstraZeneca (Inst) Isamu OkamotoHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Lilly JapanConsulting or Advisory Role: Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, PfizerResearch Funding: AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Ono Pharmaceutical (Inst), MSD Oncology (Inst), Lilly (Inst), Astellas Pharma (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Takeda (Inst), Chugai and Roche (Inst) Naoki InuiSpeakers' Bureau: Chugai Pharma, AstraZeneca and Daiichi Sankyo, Lilly, Nippon Boehringer Ingelheim, Novartis, Ono Yakuhin, Taiho PharmaceuticalResearch Funding: Chugai Pharma, Daiichi Sankyo and UCB Japan, Lilly, Nippon Boehringer Ingelheim, MSD K K, Taiho Pharmaceutical Morihito OkadaSpeakers' Bureau: Taiho Pharmaceutical, Johnson & Johnson, Covidien, Lilly, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, CSL BehringResearch Funding: Taiho Pharmaceutical (Inst), Nippon Kayaku (Inst), Chugai Pharma (Inst), Covidien (Inst), Johnson & Johnson (Inst), Daiichi Sankyo (inst), Yakult Honsha (Inst), Lilly Japan (Inst), Nihon Medi-Physics (Inst), Pfizer (Inst), Mochida Pharmaceutical Co, Ltd (Inst), Shionogi (Inst), Ono Pharmaceutical (Inst), Kyowa Hakko Kirin (Inst) Masahiro MoriseSpeakers' Bureau: Chugai and Roche, AstraZeneca, Ono Pharmaceutical, LillyResearch Funding: Boehringer Ingelheim (Inst), Novartis (Inst), AstraZeneca (Inst), Lilly (Inst), Taiho Pharmaceutical (Inst), Chugai and Roche (Inst), Ono Pharmaceutical (Inst), Pfizer (Inst), Merck Serono (Inst), Kissei Pharmaceutical (Inst) Masayuki TakedaHonoraria: AstraZeneca Japan, Chugai Pharma, Bristol Myers Squibb Company, Novartis, Ono Pharmaceutical, Boehringer Ingelheim Shunichi SugawaraHonoraria: AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, MSD K K, Yakult Honsha, Kyowa Kirin Naofumi ShinagawaResearch Funding: Olympus Kaoru KubotaHonoraria: Bristol Myers Squibb Japan, Daiichi Sankyo, Boehringer Ingelheim, Taiho Pharmaceutical, Lilly Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Nihonkayaku, Takeda, PfizerResearch Funding: Daiichi Sankyo (Inst), Boehringer Ingelheim (Inst), Taiho Pharmaceutical (Inst), Ono Pharmaceutical (Inst) Toshiaki SaekiResearch Funding: Taiho Pharmaceutical (Inst), Eisai (Inst) Tomohide TamuraHonoraria: Chugai Pharma, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, MSD, CMIC, Lilly, NihonkayakuNo other potential conflicts of interest were reported.

Background: Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients., Methods: IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting)., Findings: Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%)., Interpretation: IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC., Funding: F Hoffmann-La Roche and Genentech., Competing Interests: Declaration of interests All authors report editorial support from F Hoffmann-La Roche. EF received advisory or consulting fees from Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol–Myers Squibb, Eli Lilly, F Hoffman-La Roche, GlaxoSmithKline, Janssen, Medical Trends, Merck Sharp & Dohme (MSD), Merck Serono, Peptomyc, Pfizer, Puma, Regeneron, Sanofi, Syneos Health, and Takeda; received honoraria from Amgen, AstraZeneca, Bristol–Myers Squibb, Eli Lilly, F Hoffman-La Roche, Janssen, Medscape, Medical Trends, MSD, Merck Serono, Peervoice, Pfizer, Springer, and Touch Medical; and is an independent member of the board for and has received personal fees from GRIFOLS. NA received grants or contracts from AstraZeneca, the National Cancer Institute, New York Genome Center P1000 and LC200388 the US Department of Defense; and received honoraria from AstraZeneca and Regeneron. CZ received honoraria from Lilly China, Sanofi, Boehringer Ingelheim, Roche, MSD, Qilu, Hengrui, Innovent, C-Stone, LUYE Pharma, TopAlliance Bioscience, and Amoy Diagnostics; and participated in a data safety monitoring board or advisory board for Innovent Biologics, Hengrui, Qilu, and TopAlliance Bioscience. AM-M received personal fees and travel expenses from Bristol–Myers Squibb, F Hoffmann-La Roche, MSD, Pfizer, Boehringer Ingelheim, MSD Oncology, and AstraZeneca, outside the submitted work. HK received research funding from Chugai Pharmaceutical, Novartis Pharma KK, Daiichi-Sankyo, AstraZeneca KK; and received honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, Boehringer Ingelheim, Eli Lilly KK, Kyowa Hakko Kirin, Bristol–Myers Squibb, MSD, Novartis Pharma KK, Daiichi-Sankyo, AstraZeneca KK, Pfizer, and Taiho Pharma. SS received honoraria from Chugai Pharma. DV, YD, and MM are employed by Genentech. FW is employed by Roche (China). JY, EB, and BG are employed by Genentech and have stock ownership of F Hoffmann-La Roche. HW received research funding (to institution) from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bristol–Myers Squibb, Celgene, Clovis Oncology, Genentech/Roche, Merck, Novartis, Pharmacyclics, SeaGen, Xcovery, and Eli Lilly; received honoraria from Novartis and AstraZeneca; received compensation for advisory boards from AstraZeneca, Xcovery, Janssen, Daiichi Sankyo, Blueprint, Mirati, and Helsinn; served in an uncompensated role for advisory boards for Merck, Takeda, Genentech/Roche, and Cellworks; and reports an uncompensated leadership role with the International Association for the Study of Lung Cancer. All other authors have no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC)., Methods: This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review., Results: In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75-91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5-19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2-not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported., Conclusion: Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS., Trial Registration: The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).

Background: The current randomized, double-blind, phase 2 study assessed the efficacy and safety profile of a single intravenous administration of fosnetupitant, a neurokinin 1 receptor antagonist prodrug, for the prevention of chemotherapy-induced nausea and vomiting in Japanese patients receiving cisplatin-based chemotherapy., Methods: Patients scheduled to receive cisplatin (at a dose of ≥70 mg/m 2 )-based regimens were randomly assigned to receive fosnetupitant at a dose of 81 mg or 235 mg or placebo in combination with palonosetron at a dose of 0.75 mg and dexamethasone. The primary endpoint was complete response (CR; no vomiting and no rescue medication) during the overall phase (0-120 hours). The overall CR rate was compared between each dose of fosnetupitant and the placebo group adjusting for the stratification factors of sex and age class (age <55 years vs age ≥55 years). Safety was assessed, with special attention given to events that potentially were suggestive of infusion site reactions., Results: A total of 594 patients were randomized. Of these, 194 patients, 195 patients, and 195 patients, respectively, in the placebo and fosnetupitant 81-mg and 235-mg dose groups were evaluable for efficacy. The overall CR rate was 54.7% for the placebo group, 63.8% for the fosnetupitant 81-mg dose group (adjusted difference, 9.1%; 95% CI, -0.4% to 18.6% [P = .061]), and 76.8% for the fosnetupitant 235-mg dose group (adjusted difference, 22.0%; 97.5% CI, 11.7% to 32.3% [P < .001]). Safety profiles were comparable between the 3 groups. The incidence of infusion site reactions related to fosnetupitant was ≤1% in each dose group., Conclusions: Fosnetupitant at a dose of 235 mg provided superior prevention of chemotherapy-induced nausea and vomiting among patients receiving cisplatin-based chemotherapy compared with the control group, and with a satisfactory safety profile., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Background: Atezolizumab is effective and well-tolerated in patients with extensive-stage small-cell lung cancer (ES-SCLC), but differences in response to systemic therapy exist between Asian and Caucasian patients. Here, we assess the efficacy and tolerability of atezolizumab in Japanese patients from the IMpower133 trial (NCT02763579)., Patients and Methods: Key eligibility criteria for this multicenter, double-blind, placebo-controlled, randomized study included age ≥ 18 years; histologically or cytologically confirmed ES-SCLC, measurable per Response Evaluation Criteria in Solid Tumors version 1.1; an Eastern Cooperative Oncology Group performance status of 0/1; and no prior systemic treatment for ES-SCLC. Patients were treated with either atezolizumab 1200 mg or placebo with carboplatin (area under the curve of 5 mg/mL/min) and etoposide (100 mg/m 2 ). Primary endpoints were overall survival and investigator-assessed progression-free survival in the intention-to-treat population. Of the 403 patients randomized in the IMpower133 trial, 42 were enrolled at Japanese centers., Results: In Japanese patients in the intention-to-treat population, the median overall survival in the atezolizumab group (n = 20) was longer than that in the placebo group (n = 22; 14.6 months; 95% confidence interval [CI], 11.8-17.8 months vs. 11.9 months; 95% CI, 8.4-15.8, respectively; hazard ratio, 0.72; 95% CI, 0.31-1.67). The median progression-free survival was 4.5 months (95% CI, 4.2-8.1 months) versus 4.0 months (95% CI, 2.9-5.6 months; hazard ratio, 0.47; 95% CI, 0.23-0.96), respectively. Atezolizumab was generally well-tolerated, with no treatment-related deaths., Conclusion: The addition of atezolizumab to carboplatin and etoposide was effective and well-tolerated in Japanese patients with ES-SCLC. Results are consistent with the primary analysis of the IMpower133 trial., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The FLAURA study was a multicenter, double-blind, Phase 3 study in which patients with previously untreated epidermal growth factor receptor mutation-positive advanced non-small-cell lung carcinoma were randomized 1:1 to oral osimertinib 80 mg once daily or standard-of-care (gefitinib 250 mg or erlotinib 150 mg, once daily) to compare safety and efficacy. In the overall FLAURA study, significantly better progression-free survival was shown with osimertinib versus standard-of-care., Methods: Selected endpoints, including progression-free survival (primary endpoint), overall survival, objective response rate, duration of response and safety were evaluated for the Japanese subset of the FLAURA study., Results: In Japan, 120 eligible Japanese patients were randomized to osimertinib (65 patients) or gefitinib (55 patients) treatment from December 2014 to June 2017. Median progression-free survival was 19.1 (95% confidence interval, 12.6, 23.5) and 13.8 (95% confidence interval, 8.3, 16.6) months with osimertinib and gefitinib, respectively (hazard ratio, 0.61; 95% confidence interval, 0.38, 0.99). Median overall survival was not reached in either treatment arm (data were immature). In the osimertinib and gefitinib arms, objective response rate was 75.4% (49/65) and 76.4% (42/55), and median duration of response from onset was 18.4 (95% confidence interval, not calculated) and 9.5 (95% confidence interval, 6.2, 13.9) months, respectively. The incidence of adverse events was similar in the two groups. The frequency of Grade ≥3 interstitial lung disease and pneumonitis in the two groups were the same (one patient)., Conclusions: As the first-line therapy, osimertinib showed significantly improved efficacy versus gefitinib in the Japanese population of the FLAURA study. No new safety concerns were raised., Clinical Trial Registration: NCT02296125 (ClinicalTrials.gov).

Epidermal growth factor receptor (EGFR) activating mutations occur in approximately 50% of East Asian patients with non-small-cell lung cancer (NSCLC) and confer sensitivity to tyrosine kinase inhibitors (TKIs). ASP8273 is an irreversible EGFR-TKI, given orally, that inhibits EGFR activating mutations and has shown clinical activity in patients with EGFR mutation-positive NSCLC. Epidermal growth factor receptor-TKI-naïve Japanese adult patients (≥20 years) with NSCLC harboring EGFR mutations were enrolled in this open-label, single-arm, phase II study (ClinicalTrials.gov identifier NCT02500927). Patients received ASP8273 300 mg once daily until discontinuation criteria were met. The primary end-point was to determine the safety of ASP8273 300 mg; the secondary end-point was antitumor activity defined by RECIST version 1.1. Thirty-one patients (12 men and 19 women; median age, 64 years [range, 31-82 years]) with EGFR mutation-positive NSCLC were enrolled; as of 23 February 2016, 25 patients (81%) were still on study. Of the 31 patients, 27 (87%) had an exon 19 deletion (n = 13, 42%) or an L858R (n = 14, 45%) EGFR activating mutation, and two (7%) had an L861Q mutation. Five patients (16%) had other EGFR activating mutations, two had an activating mutation and the T790M resistance mutation. The most commonly reported treatment-emergent adverse event was diarrhea (n = 24, 77%). All patients had at least one post-baseline scan; one patient (3%) achieved a confirmed complete response, 13 (42%) had a confirmed partial response, and 15 (48%) had confirmed stable disease (disease control rate, 94% [n = 29/31]) per investigator assessment. Once-daily ASP8273 at 300 mg was generally well tolerated and showed antitumor activity in TKI-naïve Japanese patients with EGFR mutation-positive NSCLC., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Our recent studies revealed that dual strands of certain pre-microRNAs, e.g., pre- miR-144 , pre- miR-145 , and pre- miR-150 , act as antitumor microRNAs (miRNAs) in several cancers. The involvement of passenger strands of miRNAs in cancer pathogenesis is a novel concept in miRNA research. The analysis of a miRNA expression signature in clear cell renal cell carcinoma (ccRCC) has revealed that the guide strand of pre- miR-149 is significantly downregulated in cancer tissues. The aims of this study were to investigate the functional significance of miR-149 's guide strand ( miR-149-5p ) and passenger strand ( miR-149-3p ), and to identify the oncogenic genes regulated by these miRNAs in ccRCC cells. The ectopic expression of these miRNAs significantly inhibited cancer cell migration and invasion in ccRCC cells. Forkhead box protein M1 (FOXM1) was directly regulated by miR-149-5p and miR-149-3p in ccRCC cells. Knockdown studies using si-FOXM1 showed that the expression of FOXM1 enhanced RCC cell aggressiveness. Interestingly, the analysis of a large number of patients in the The Cancer Genome Atlas (TCGA) database (n = 260) demonstrated that patients with high FOXM1 expression had significantly shorter survival than did those with low FOXM1 expression (p = 1.5 × 10⁻⁶). Taken together, dual strands of pre-miR-149 (miR-149-5p and miR-149-3p) acted as antitumor miRNAs through the targeting of FOXM1 in ccRCC cells., Competing Interests: The authors declare no conflicts of interests.

Malignant mesothelioma is an aggressive cancer with limited therapeutic options. Sialic acid-binding lectin isolated from Rana catesbeiana oocytes (cSBL) is a multifunctional protein with anti-cancer activity. The effects of pemetrexed, cisplatin, and cSBL were evaluated in mesothelioma and normal mesothelial cell lines. We evaluated cytotoxicity, apoptosis, caspase-3 cleavage and activation, cell proliferation, cell cycle arrest, and levels of cell cycle proteins in H28 cells treated with pemetrexed, cisplatin, and cSBL alone or in combination. Treatment with cSBL alone was cytotoxic to mesothelioma cells. The anti-cancer effect of cSBL was observed in a broader range of cell lines and exhibited greater cancer cell selectivity than pemetrexed or cisplatin. Combination treatment with pemetrexed + cSBL resulted in greater dose-dependent cytotoxicity than pemetrexed + cisplatin, the standard of care in mesothelioma. The synergistic effect of pemetrexed + cSBL was mediated by the cytostatic effect of pemetrexed and the cytotoxic effect of cSBL. It thus appears that cSBL has therapeutic potential for the treatment of mesothelioma.

An N-acetyl sugar-binding lectin (termed iNoL) displaying cytotoxic activity against human cancer cells was isolated from the slipper lobster Ibacus novemdentatus (family Scyllaridae). iNoL recognized monosaccharides containing N-acetyl group, and glycoproteins (e.g., BSM) containing oligosaccharides with N-acetyl sugar. iNoL was composed of five subunits (330, 260, 200, 140, and 30 kDa), which in turn consisted of 70-, 40-, and 30-kDa polypeptides held together by disulfide bonds. Electron microscopic observations and gel permeation chromatography indicated that iNoL was a huge (500-kDa) molecule and had a polygonal structure under physiological conditions. iNoL displayed cytotoxic (apoptotic) effects against human cancer cell lines MCF7 and T47D (breast), HeLa (ovarian), and Caco2 (colonic), through incorporation (internalization) into cells. The lectin was transported into lysosomes via endosomes. Its cytotoxic effect and incorporation into cells were inhibited by the co-presence of N-acetyl-D-mannosamine (ManNAc). Treatment of HeLa cells with iNoL resulted in DNA fragmentation and chromatin condensation, through activation of caspase-9 and -3. In summary, the novel crustacean lectin iNoL is incorporated into mammalian cancer cells through glycoconjugate interaction, and has cytotoxic (apoptotic) effects.

Silurus asotus egg lectin (SAL), an α-galactoside-binding protein isolated from the eggs of catfish, is a member of the rhamnose-binding lectin family that binds to Gb3 glycan (Galα1-4Galβ1-4Glc). We have previously demonstrated that SAL reduces the proliferation of Gb3-expressing Burkitt's lymphoma Raji cells and confirm here that it does not reduce their viability, indicating that unlike other lectins, it is not cytotoxic. The aim of this study was to determine the signal transduction mechanism(s) underlying this novel SAL/Gb3 binding-mediated effect profile. SAL/Gb3 interaction arrested the cell cycle through increasing the G 0/1 phase population of Raji cells. SAL suppressed the transcription of cell cycle-related factors such as c-MYC, cyclin D3, and cyclin-dependent protein kinase (CDK)-4. Conversely, the CDK inhibitors p21 and p27 were elevated by treatment with SAL. In particular, the production of p27 in response to SAL treatment increased steadily, whereas p21 production was maximal at 12 h and lower at 24 h. Activation of Ras-MEK-ERK pathway led to an increase in expression of p21. Notably, treatment of Raji cells with anti-Gb3 mAb alone did not produce the above effects. Taken together, our findings suggest that Gb3 on the Raji cell surface interacts with SAL to trigger sequential GDP-Ras phosphorylation, Ras-MEK-ERK pathway activation, p21 production, and cell cycle arrest at the G 0/1 phase.

Background: The epidermal growth factor receptor (EGFR) T790M mutation is considered the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations. Although chemotherapy is commonly used for those patients under the condition without T790M-targeted therapy, the clinical outcomes are poorly defined. Therefore, we aimed to reveal the treatment patterns and clinical outcomes in patients with T790M-positive NSCLC., Methods: We conducted a retrospective observational study at 23 sites in Japan, and 141 patients with T790M-positive advanced/recurrent NSCLC were identified from January 2008 to December 2014. Their records were studied to understand treatment patterns after detection of a T790M mutation and to assess the objective response rate (ORR) and median survival time (MST) to specific treatment modalities., Results: Of 141 patients, 24 had de novo T790M-positive tumors and 117 had acquired T790M-positive tumors, with MSTs (95% CI) of 21.4 (12.4-36.7) and 9.1 (6.4-13.9) months, respectively. The most common regimen was platinum-based doublet chemotherapy ± bevacizumab, which was associated with an ORR/MST of 25.0%/29.1 months, respectively, in patients with de novo T790M mutations, and 22.2%/15.3 months, respectively, in patients with acquired T790M mutations., Conclusions: This study reveals the treatment patterns and outcomes of NSCLC patients in Japan after detection of the T790M mutation. The most common treatment following detection of the T790M mutation was platinum-based doublet chemotherapy ± bevacizumab. Platinum-based doublet chemotherapy ± bevacizumab was moderately effective, indicating the need for targeted therapies for patients with T790M mutation-positive NSCLC., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The epidermal growth factor receptor (EGFR) tyrosine kinase has been an important target for non-small-cell lung cancer. Several EGFR tyrosine kinase inhibitors (TKIs) are currently approved, and both gefitinib and erlotinib are the most well-known first-generation EGFR-TKIs. This randomized phase III study was conducted to investigate the difference between these two EGFR-TKIs., Patients and Methods: Previously treated patients with lung adenocarcinoma were randomly assigned to receive gefitinib or erlotinib. This study aimed to investigate the noninferiority of gefitinib compared with erlotinib. The primary end point was progression-free survival (PFS)., Results: Five hundred sixty-one patients were randomly assigned, including 401 patients (71.7%) with EGFR mutation. All baseline factors (except performance status) were balanced between the arms. Median PFS and overall survival times for gefitinib and erlotinib were 6.5 and 7.5 months (hazard ratio [HR], 1.125; 95% CI, 0.940 to 1.347; P = .257) and 22.8 and 24.5 months (HR, 1.038; 95% CI, 0.833 to 1.294; P = .768), respectively. The response rates for gefitinib and erlotinib were 45.9% and 44.1%, respectively. Median PFS times in EGFR mutation-positive patients receiving gefitinib versus erlotinib were 8.3 and 10.0 months, respectively (HR, 1.093; 95% CI, 0.879 to 1.358; P = .424). The primary grade 3 or 4 toxicities were rash (2.2% for gefitinib v 18.1% for erlotinib) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation (6.1%/13.0% for gefitinib v 2.2%/3.3% for erlotinib)., Conclusion: The study did not demonstrate noninferiority of gefitinib compared with erlotinib in terms of PFS in patients with lung adenocarcinoma according to the predefined criteria., (© 2016 by American Society of Clinical Oncology.)

Background: Bevacizumab combined with platinum-based chemotherapy has been established as a standard treatment option in the first-line setting for advanced nonsquamous non-small cell lung cancer (NSCLC). However, there has been no evidence to support the use of bevacizumab beyond disease progression in such patients., Methods: West Japan Oncology Group 5910L was designed as a multicenter, open-label, randomized, phase 2 trial of docetaxel versus docetaxel plus bevacizumab every 3 weeks for patients with recurrent or metastatic nonsquamous NSCLC whose disease had progressed after first-line treatment with bevacizumab plus a platinum-based doublet. The primary endpoint was progression-free survival (PFS)., Results: One hundred patients were randomly assigned to receive docetaxel (n = 50) or docetaxel plus bevacizumab (n = 50), and this yielded median PFS times of 3.4 and 4.4 months, respectively, with a hazard ratio (HR) of 0.71 and a stratified log-rank P value of .058, which met the predefined criterion for statistical significance (P < .2). The median overall survival also tended to be longer in the docetaxel plus bevacizumab group (13.1 months; 95% confidence interval [CI], 10.6-21.4 months) versus the docetaxel group (11.0 months; 95% CI, 7.6-16.1 months) with an HR of 0.74 (95% CI, 0.46-1.19; stratified log-rank P = .11). No unexpected or severe adverse events were recorded., Conclusions: Further evaluation of bevacizumab beyond disease progression is warranted for patients with advanced NSCLC whose disease has progressed after treatment with bevacizumab plus a platinum-based doublet., (© 2016 American Cancer Society.)

Objectives. To evaluate the efficacy and safety of personalized peptide vaccination (PPV) combined with chemotherapy for patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and Methods. Previously treated PS0-1 patients with IIIB/IV EGFR (epidermal growth factor receptor) wild genotype NSCLC were randomly assigned to docetaxel (60 mg/m(2) on Day 1) plus PPV based on preexisting host immunity or docetaxel plus placebo. Docetaxel administration was repeated every 3 weeks until disease progression. Personalized peptides or placebo was injected subcutaneously weekly in the first 8 weeks and biweekly in subsequent 16 weeks. The primary efficacy endpoint was progression-free survival (PFS). Results. PPV related toxicity was grade 2 or less skin reaction. The median PFS for placebo arm and PPV arm was 52 days and 59 days, respectively. There was no significant difference between two arms by log-rank test (p = 0.42). Interestingly, PFS and overall survival (OS) in humoral immunological responder were significantly longer than those in nonresponder. Conclusion. PPV did not improve the survival in combination with docetaxel for previously treated advanced NSCLC. However, PPV may be efficacious for the humoral immunological responders and a further clinical investigation is needed.

Purpose: Amrubicin and re-challenge of platinum doublet are both effective treatments for sensitive-relapsed small-cell lung cancer (SCLC). However, no comparative study of these treatments has been reported. This randomized study was conducted to select the most suitable regimen for future evaluation., Patients and Methods: SCLC patients who had relapsed more than 90 days after their first-line platinum-doublet regimen were randomized to receive amrubicin (40mg/m(2), days 1-3) or re-challenge with platinum doublet. Primary endpoint was objective response rate (ORR), with secondary endpoints of progression-free survival (PFS), overall survival and toxicity profiles. We assumed that an ORR of 50% indicates potential usefulness, while that of 30% would constitute the lower limit of interest (alpha 0.1; beta 0.1). Initial estimated accrual was 28 patients to each arm., Results: From February 2008 to June 2013, 60 patients were enrolled and 57 patients (27 amrubicin and 30 re-challenge) were found to be evaluable for efficacy and safety. The ORR and PFS were 67% (90% confidence interval, 52-82) and 5.4 months in the amrubicin group, and 43% (90% confidence interval, 28-58) and 5.1 months in the re-challenge group, respectively. Although grade 3 febrile neutropenia was observed in 19% of patients in the amrubicin group, these episodes were transient and manageable. Non-hematological toxicities were generally moderate and no treatment-related death was observed in either group., Conclusion: Only amrubicin met the primary endpoint. Moreover, amrubicin demonstrated superior efficacy over re-challenge of platinum with acceptable levels of toxicity. Further evaluation of amrubicin for sensitive-relapsed SCLC is warranted., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess outcomes of elderly patients with advanced NSCLC harboring an EGFR mutation treated with gefitinib, as well as safety and impact on quality of life (QoL)., Methods: We performed a retrospective analysis of pooled data from one Phase III and two Phase II studies of 71 patients aged ≥ 70 years with a performance status of 0 - 2. The main outcome measures were progression-free survival (PFS), overall survival (OS) and response rate (RR), as well as incidence of adverse events and time to 9.1% deterioration in QoL., Results: Median PFS (14.3 vs 5.7 months, p < 0.001) and overall RR (73.2 vs 26.5%, p < 0.001) in the gefitinib group were superior to those in the standard chemotherapy group, whereas median OS was not significantly different (30.8 vs 26.4 months, p = 0.42). Elevation of aspartate transaminase and/or alanine transaminase (18.3%) was the most common adverse event, and one treatment-related death (pneumonitis) occurred. Time to 9.1% deterioration in the QoL domains of pain and dyspnea, anxiety, and daily functioning was similar between the two age groups., Conclusion: First-line gefitinib is efficacious with acceptable toxicity in relatively fit elderly patients with advanced NSCLC harboring an EGFR mutation.

Heat shock proteins (Hsps) are molecular chaperones that maintain homeostasis of organisms. In regards to the Hsps, many studies have investigated the structure, expression, localization and functions of Hsp70 and Hsc70 including expression in the glycosphingolipid-enriched microdomain (GEM) on the cell surface and involvement in cell death. Sialic acid-binding lectin (SBL) isolated from oocytes of Rana catesbeiana is a multifunctional protein which has lectin activity, ribonuclease activity and antitumor activity. SBL has potential as a new type of anticancer drug, since it causes cancer-selective induction of apoptosis by multiple signaling pathways in which RNA is its target; and the participation of the mitochondrial pathway and the endoplasmic reticulum (ER) stress-mediated pathway has been suggested. It has also been suggested that receptor(s) for SBL (SBLR) may exist in the GEM on the cell surface. In the present study, we studied the possible involvement of Hsp70 and Hsc70 in SBL-induced apoptosis. We showed that Hsp70 and Hsc70 were expressed on the P388 cell surface similar to SBLR, and their distribution in cells dramatically changed immediately prior to the execution of apoptosis following stimulation of SBL. Functional study of Hsp70 revealed that decreased expression of Hsp70 diminished the apoptosis induced by SBL. It is suggested that Hsp70 participates in the antitumor effect of SBL.

Sialic acid-binding lectin (SBL), isolated from oocytes of Rana catesbeiana, is leczyme and has both lectin and ribonuclease (RNase) activities. A remarkable antitumor effect of SBL has also been reported. SBL agglutinates various kinds of tumor cells but not normal cells. SBL agglutination activity is not affected by mono- or oligosaccharides. However, SBL-induced agglutination and antitumor effects are inhibited by sialomucin but not asialomucin. In addition, SBL has very little effect on sialidase-treated cells. SBL causes cancer-selective induction of apoptosis by multiple signaling pathways, which target RNA. Synergistic antitumor effects with other molecules, such as tumor necrosis factor-related apoptosis ligand (TRAIL) and interferon- γ (IFN-γ), have been reported. Thus, SBL may be a novel candidate molecule for anticancer drug development. Sialoglycoconjugates on the tumor cell surface may be associated with lectin activity and antitumor effects of SBL. We review the properties of SBL, particularly its lectin, RNase, and antitumor activities, and comprehensively examine the potential application of SBL for clinical purposes.

De novo lipogenesis is activated in most cancers. Inhibition of ATP citrate lyase (ACLY), the enzyme that catalyzes the first step of de novo lipogenesis, leads to growth suppression and apoptosis in a subset of human cancer cells. Herein, we found that ACLY depletion increases the level of intracellular reactive oxygen species (ROS), whereas addition of an antioxidant reduced ROS and attenuated the anticancer effect. ACLY depletion or exogenous hydrogen peroxide induces phosphorylation of AMP-activated protein kinase (p-AMPK), a crucial regulator of lipid metabolism, independently of energy status. Analysis of various cancer cell lines revealed that cancer cells with a higher susceptibility to ACLY depletion have lower levels of basal ROS and p-AMPK. Mitochondrial-deficient ρ(0) cells retained high levels of ROS and p-AMPK and were resistant to ACLY depletion, whereas the replenishment of normal mitochondrial DNA reduced the levels of ROS and p-AMPK and restored the sensitivity to ACLY depletion, indicating that low basal levels of mitochondrial ROS are critical for the anticancer effect of ACLY depletion. Finally, p-AMPK levels were significantly correlated to the levels of oxidative DNA damage in colon cancer tissues, suggesting that p-AMPK reflects cellular ROS levels in vitro and in vivo. Together, these data suggest that ACLY inhibition exerts an anticancer effect via increased ROS, and p-AMPK could be a predictive biomarker for its therapeutic outcome., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

To develop novel inhibitors of P-glycoprotein (P-gp), dimeric peptides related to an opioid peptide containing the Dmt-Tic pharmacophore were synthesized and their P-gp inhibitory activities were analyzed. Of the 30 analogs synthesized, N(α),N(ε)-[(CH(3))(2)Mle-Tic](2)Lys-NH(2) and its D-Lys analog were found to exhibit potent P-gp inhibitory activity, twice that of verapamil, in doxorubicin-resistant K562 cells. Structure-activity studies indicated that the correct hydrophobicity and spacer length between two aromatic rings are important structural elements in this series of analogs for inhibition of P-gp., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A novel anticancer mechanism of catfish (Silurus asotus) egg lectin (SAL) was found to occur via the down-regulation of the membrane transopter protein, MRP1 (multidrug resistance associate protein-1) on Burkitt's lymphoma cells through Gb3(Galα1-4Galβ1-4Glc)-glycosphingolipid. Although SAL did not influence the viability of the cells directly, only 10 and 100 ng/mL of vincristine and etoposide, respectively induced anticancer effects when the lectin was applied in conjunction with these drugs. These phenomena were specifically inhibited by the co-presence of the α-galactoside, melibiose, which is a strong haptenic sugar of SAL that mimicks Gb3. The degree of expression regulation of the transporter proteins on the cells surface was investigated through the examination of the binding between SAL and Gb3-glycosphingolipid by immunological and molecular biological procedures. PCR data showed that MRP1 was more highly expressed when compared to another ATP-binding cassette family, multi-drug resistant protein and the expression levels of MRP1 on the cells were specifically dose- and time-dependently depleted by the addition of SAL. These results were also evaluated by immunological procedures using FACS and western-blotting. Small interfering RNA coding a part of MRP1 was transfected to Raji cells to knock down the protein, and cell death was increased by 10% when vincristine was administered at a concentration as low as 10 ng/mL compared to non-transfected cells. These results indicated that SAL possesses the potential to enhance the anticancer activites of low-concentrations of vincristine by the down-regulating the MRP1 gene expression to inhibit the multidrug resistance by binding to the target ligand Gb3-glycosphingolipid on Burkitt's lymphoma cells.

Background: For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, first-line gefitinib produced a longer progression-free survival interval than first-line carboplatin plus paclitaxel but did not show any survival advantage in the North East Japan 002 study. This report describes the quality of life (QoL) analysis of that study., Methods: Chemotherapy-naïve patients with sensitive EGFR-mutated, advanced NSCLC were randomized to receive gefitinib or chemotherapy (carboplatin and paclitaxel). Patient QoL was assessed weekly using the Care Notebook, and the primary endpoint of the QoL analysis was time to deterioration from baseline on each of the physical, mental, and life well-being QoL scales. Kaplan-Meier probability curves and log-rank tests were employed to clarify differences., Results: QoL data from 148 patients (72 in the gefitinib arm and 76 in the carboplatin plus paclitaxel arm) were analyzed. Time to defined deterioration in physical and life well-being significantly favored gefitinib over chemotherapy (hazard ratio [HR] of time to deterioration, 0.34; 95% confidence interval [CI], 0.23-0.50; p < .0001 and HR, 0.43; 95% CI, 0.28-0.65; p < .0001, respectively)., Conclusion: QoL was maintained much longer in patients treated with gefitinib than in patients treated with standard chemotherapy, indicating that gefitinib should be considered as the standard first-line therapy for advanced EGFR-mutated NSCLC in spite of no survival advantage.

We have used glutathione for prevention of oxaliplatin-related neurotoxicity with reference to the article of Cascinu et al. We investigated oxaliplatin-related neurotoxicity in Kariya Toyota General Hospital(KTGH)and compared with the data described in the article of Gamelin about the severity of its neurotoxicity. Grade 3 neurotoxicity was observed in only 5 of 44 patients(11.4%). The median number of cycles and cumulative dose of oxaliplatin were 12 cycles(5-27 / cycles)and 802.2(273.2-1,952.4)mg/m(2), respectively, at Grade 3 neuropathy. We evaluated retrospectively neuro-toxicity grade at cumulative oxaliplatin doses of approximately 500-520 mg/m(2). The severity of neurotoxicity observed in KTGH was significantly lower than in the group without Ca/Mg. We found no difference between the group with glutathione and / with Ca/Mg. Glutathione infusions seemed to prevent oxaliplatin-related neurotoxicity.

We report a case of angiosarcoma of the right atrium presenting superior vena cava syndrome. The patient was a 61-year-old man. Echocardiography, CT and MRI revealed a tumor arising in the anterior wall of the right atrium. The tumor was hen-egg sized and unresectable because of the invasion of the pericardium, the right ventricular wall and the superior vena cava. An open biopsy and left brachiocephalic vein-right atrium bypass grafting were performed. The pathological diagnosis was angiosarcoma. The patient agreed to chemotherapy with docetaxel, which is known to be often effective against angiosarcoma of the scalp or face. After 5 courses of docetaxel administration (30 mg/m2 on day 1, 8 and 15 followed by 14 days. rest as one course), echocardiography and CT showed a remarkable tumor reduction, which was evaluated as a partial response. The chemotherapy was suspended for 8 months because of neutropenia and general fatigue as side effects of docetaxel. The administration of docetaxel was resumed and 4 courses were performed. The tumor, however, became resistant to docetaxel and formed metastatic involvements in the liver. Following treatments with paclitaxel, IL-2 and CPT-11 were ineffective for the primary tumor and liver metastases. He died of cardiac tamponade caused by massive hemorrhage into the pericardiac space from the tumor surface. He had long-term survival 31 months after the diagnosis. An effective treatment for cardiac angiosarcoma has not yet been established. Chemotherapy with docetaxel should be considered in the treatment of patients with cardiac angiosarcoma.

Recombinant adenovirus mediated p53 gene transfer combined with anti-cancer drugs has clinical potential for gene therapy of lung cancer. We constructed a recombinant adenoviral vector expressing wild-type p53 cDNA (Ad-p53), and assessed the efficacy of a combined treatment with Ad-p53 and six anti-cancer drugs (cisplatin, 5-fluorouracil, doxorubicin, docetaxel, irinotecan, and etoposide) for human lung cancer cell lines, H1299 (with deleted p53), RERF-LC-OK (with mutant p53), and A549 (with wild-type p53). The infection of the Ad-p53 vector into H1299 cells, RERF-LC-OK cells, or A549 cells increased the sensitivity to all six drugs regardless of the cellular p53 status, and a synergism was observed by the isobolic method in combination studies (D<1). We conclude that our strategy using adenoviral mediated p53 gene transfer to cancer cells can enhance the cytotoxic effect of anti-cancer drugs, which leading to an improvement of lung cancer chemotherapy.

Protein kinase C (PKC) regulates many cellular processes. In view of its possible relevance to the drug resistance, the levels of PKC activity were assessed in human leukemia cell lines with reference to the sensitivity to antineoplastic agents. K562/ADM exhibited approximately 2-fold higher levels of PKC activity as compared with the parental K562. After a 1-hr preincubation with Adriamycin (ADM) (0.5, 1, 10 microM), PKC activity in K562 tended to increase dose-dependently, while no substantial alteration was found in K562/ADM. Cisplatin (CDDP) or etoposide was of no effect. The activity in THP-1/E was slightly lower than THP-1, and the basal level stayed unchanged with any one of the above drugs. These results suggest that in K562 increase in PKC activity with ADM may play a role in the process of acquisition of resistance.

Background: The optimal platinum doublet regimen in elderly patients with non-small-cell lung cancer (NSCLC) is still uncertain. We conducted a randomized phase II study to compare the efficacy and safety of weekly paclitaxel combined with carboplatin with those of the standard schedule. [ABSTRACT FROM PUBLISHER]

Many patients with metastatic non-small-cell lung cancer (mNSCLC) experience disease progression after first- and second-line treatment; more treatment options are required for these patients. ARCTIC, a phase III, randomized, open-label study, assessed durvalumab ± tremelimumab versus standard of care (SoC) as ≥ third-line treatment of mNSCLC. ARCTIC comprised two independent sub-studies. Study A: 126 patients with ≥25% of tumor cells (TCs) expressing programmed cell death ligand-1 (PD-L1) were randomized (1 : 1) to durvalumab [up to 12 months 10 mg/kg every 2 weeks (q2w)] or SoC. Study B: 469 patients with PD-L1 TC <25% were randomized (3 : 2 : 2 : 1) to durvalumab + tremelimumab (12 weeks durvalumab 20 mg/kg + tremelimumab 1 mg/kg q4w then 34 weeks durvalumab 10 mg/kg q2w), SoC, durvalumab (up to 12 months 10 mg/kg q2w), or tremelimumab (24 weeks 10 mg/kg q4w then 24 weeks q12w). Primary end points: overall survival (OS) and progression-free survival (PFS) for durvalumab versus SoC (study A; descriptive only) and durvalumab + tremelimumab versus SoC (study B). Study A: median OS 11.7 (durvalumab) versus 6.8 (SoC) months {hazard ratio (HR) 0.63 [95% confidence interval (CI), 0.42–0.93]}; median PFS 3.8 (durvalumab) versus 2.2 (SoC) months [HR 0.71 (95% CI, 0.49–1.04)]. Study B: median OS 11.5 (durvalumab + tremelimumab) versus 8.7 (SoC) months [HR 0.80 (95% CI, 0.61–1.05); P = 0.109]. Median PFS of 3.5 months for both groups [HR 0.77 (95% CI, 0.59–1.01); P = 0.056]. Treatment-related grade 3/4 adverse events: 9.7% (durvalumab) and 44.4% (SoC; study A) and 22.0% (durvalumab + tremelimumab) and 36.4% (SoC; study B). In heavily pretreated patients with mNSCLC, durvalumab demonstrated clinically meaningful improvements in OS and PFS versus SoC (patients with PD-L1 TC ≥25%); numerical improvements in OS and PFS for durvalumab + tremelimumab versus SoC were observed (patients with PD-L1 TC <25%). Safety profiles were consistent with previous studies. Clinicaltrials.gov identifier: NCT02352948. • The phase III ARCTIC study evaluated durvalumab ± tremelimumab versus SoC in heavily pretreated patients with metastatic NSCLC • Durvalumab monotherapy showed clinically meaningful improvements in OS and PFS versus SoC in patients with PD-L1 TC ≥25% • Durvalumab + tremelimumab showed numerical improvements in OS and PFS versus SoC in patients with PD-L1 TC <25% • Safety profiles of durvalumab and tremelimumab were consistent with previous studies [ABSTRACT FROM AUTHOR]